This invention relates generally to the handling and processing of solid supports, such as beads. More specifically, the invention relates to systems and techniques for placing solid supports into an organized array.
In modem chemistry, large libraries of chemical compounds are often created from which certain compounds which are of interest may be identified. The creation of such libraries may be accomplished with a synthesizing process where various compounds are placed on solid supports, such as spherical beads. Such processes are well known within the art, and are described in, for example, U.S. Pat. No. 5,503,805, the complete disclosure of which is herein incorporated by reference.
After synthesis, it is often desirable to analyze the compounds synthesized on the beads. One such process is by placing an assortment of beads in an assay solution and observing whether a chemical reaction occurs. For example, groups of beads which include synthesized chemicals may initially be placed into a plurality of wells where a portion of the compound on the beads is photo-chemically released. Assays are then performed on each well. For wells producing a positive result, the groups of beads are then transferred into another well or are further divided and placed into a plurality of wells so that further testing can occur to identify the compound. Hence, to successfully perform such assays, the beads need to be transferred to different locations.
When handling such beads, the beads are usually held within a liquid medium, such as water, to help prevent (among other reasons) the beads from sticking together. Usually, such beads are very small, e.g. on the order of about 5 xcexcm to 300 xcexcm. As such, transferring of such small beads from one location to another while held within a liquid medium may be difficult and challenging. Transferring such small beads is especially challenging when a known quantity of beads, such as a single bead, must be individually transferred from a group of beads and placed in a test well. Further, it is often convenient to separate the beads into arrays that are compatible with automated screening systems. For example, much of the automated equipment now uses standard footprints, such as 96 well plates, 864 well plates, and the like.
Exemplary techniques for separating and organizing solid supports are described in, for example, U.S. Pat. No. 5, 722,470 and U.S. patent application Ser. No. 08/637,123, filed Apr. 24, 1996, the complete disclosures of which are herein incorporated by reference. The invention is related to other techniques for separating solid supports and placing the solid supports into an organized array. The techniques of the invention permit the transferring of a single bead, or a known quantity of beads, in a repeatable manner.
The invention provides for the transfer of solid supports from one location to another. One particular feature of the invention is the ability to transfer a known quantity of solid supports in a repeatable and efficient manner. In one embodiment, a system for processing a plurality of solid supports comprises a tubular member having a proximal end, a distal end, and a lumen terminating at the distal end. A stop is positioned with the lumen at a location spaced above the distal end and is sized to permit fluids to pass through the lumen while preventing the passage of solid supports. A fluid transfer device is provided to transfer fluids through the lumen such that when a fluid containing multiple solid supports is aspirated into the lumen, one or more solid supports may be drawn into the lumen until lodging against the stop. Hence, a known quantity of solid supports may be captured within the lumen simply by adjusting the position of the stop relative to the distal end of the tubular member. Once the solid supports are captured, the tubular member may be transferred to another location and the solid supports expelled by forcing liquids out of the distal end using the fluid transfer device.
In one particular aspect, the fluid transfer device comprises a syringe pump and a length of tubing coupling the syringe pump to the tubular member. In this way, the syringe pump may be operated to aspirate fluids into the tubular member to capture one or more solid supports into the lumen, and to irrigate fluids from the tubular member to expel any captured solid supports. Conveniently, a source of fluid may be coupled to the syringe pump.
In another particular aspect, the stop comprises a wire that is slidable within the lumen to permit the spacing between the distal end of the wire and the distal end of the tubular member to be adjusted. In this way, the number of potential solid supports that may be captured within a lumen may easily be adjusted.
In still another aspect, a reservoir is provided having a plurality of solid supports. A moving mechanism is also provided to move the tubular member relative to the reservoir to permit placement of the distal end of the tubular member into the reservoir. The system may also include a plate having a plurality of wells, and the moving mechanism may be configured to move the tubular member relative to the plate to permit any solid supports to be expelled from the tubular member and into the wells of the plate. In one particular aspect, the moving mechanism comprises a movable arm to move the tubular member along the Z axis, and a movable stage onto which the reservoir and the plate are held. The stage is movable along the X and Y axes so that the plate may be appropriately positioned relative to the tubular member. Conveniently, a controller may be provided to control operation of the fluid transfer device and the moving mechanism.
Advantageously, the system may include a plurality of tubular members that each have a lumen and a stop disposed within the lumen in a manner similar to that just described. A manifold may be coupled to each of the tubular members, with the fluid transfer device being coupled to the manifold. In this way, the throughput of the system may be greatly increased by introducing the tubular members into an array of reservoirs so that each tubular member may capture one or more solid supports.
In another particular aspect, the lumen may have a diameter in the range from about 190 xcexcm to about 210 xcexcm, and the solid supports may have a mean diameter in the range from about 120 xcexcm to about 140 xcexcm. Further, the wire may have an outer diameter in the range from about 125 xcexcm to about 150 xcexcm to permit fluids to pass between the wire and the tubular member when aspirating and irrigating fluids. However, it will be appreciated that other sizes may be used. For example, in some cases the lumen may have a diameter in the range from about 100 xcexcm to about 250 xcexcm.
The invention further provides an exemplary method for processing solid supports having at least one chemical that is synthesized onto the solid supports. According to the method, a tubular member is provided having a proximal end, a distal end, and a lumen terminating at the distal end. A stop is positioned within the lumen at a location spaced above the distal end. The distal end of the tubular member is placed into a fluid having a plurality of solid support, and at least some of the fluid is aspirated into the lumen. The aspirated fluid travels past the stop to draw at least one of the solid supports into the lumen until lodging against the stop. The liquid may be aspirated for a time sufficient to permit the space between the stop and the distal end to be filled with a linear array of solid supports. For example, the tubular member may be employed to capture about one to about 10 solid supports within the lumen, although in some cases larger amounts may be captured.
After the solid supports have been captured within the lumen, the tubular member may be removed from the liquid and transferred to another location. Fluid may then be forced through the lumen and past the stop to expel the solid supports from the tubular member. Conveniently, the fluid and the solid supports may be held within a reservoir, and the tubular member may be moved relative to the reservoir to place the distal end into the fluid. After removing the tubular member from the reservoir, the tubular member may be moved over a multi-well plate to permit the solid supports to be expelled into one of the wells of the plate.
In another aspect, the lumen may be primed with a fluid to remove substantially all gas bubbles from the lumen prior to aspirating the fluid. In another aspect, multiple tubular members may be provided that each have a lumen and a stop within the lumen. In this way, a distal end of each of the tubular members may be simultaneously introduced into the fluid, and fluid aspirated into each of the lumens to draw at least one solid support into each of the lumens.